Flolan

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Adverse Events During Dose Initiation and Escalation

During early clinical trials, FLOLAN (epoprostenol sodium) was increased in 2-ng/kg/min increments
until the patients developed symptomatic intolerance. The most common adverse
events and the adverse events that limited further increases in dose were generally
related to vasodilation, the major pharmacologic effect of FLOLAN (epoprostenol sodium) . The most
common dose-limiting adverse events (occurring in ≥ 1% of patients) were nausea,
vomiting, headache, hypotension, and flushing, but also include chest pain,
anxiety, dizziness, bradycardia, dyspnea, abdominal pain, musculoskeletal pain,
and tachycardia. Table 3 lists the adverse events reported during dose initiation
and escalation in decreasing order of frequency.

Table 3: Adverse Events During Dose Initiation and Escalation

Adverse Events Occurring in ≥ 1% of Patients

FLOLAN
(n = 391)

Flushing

58%

Headache

49%

Nausea/vomiting

32%

Hypotension

16%

Anxiety, nervousness, agitation

11%

Chest pain

11%

Dizziness

8%

Bradycardia

5%

Abdominal pain

5%

Musculoskeletal pain

3%

Dyspnea

2%

Back pain

2%

Sweating

1%

Dyspepsia

1%

Hypesthesia/paresthesia

1%

Tachycardia

1%

Adverse Events During Chronic Administration

Interpretation of adverse events is complicated by the clinical features of
PAH, which are similar to some of the pharmacologic effects of FLOLAN (epoprostenol sodium) (e.g.,
dizziness, syncope). Adverse events which may be related to the underlying disease
include dyspnea, fatigue, chest pain, edema, hypoxia, right ventricular failure,
and pallor. Several adverse events, on the other hand, can clearly be attributed
to FLOLAN (epoprostenol sodium) . These include hypotension, bradycardia, tachycardia, pulmonary edema,
bleeding at various sites, thrombocytopenia, headache, abdominal pain, pain
(unspecified), sweating, rash, arthralgia, jaw pain, flushing, diarrhea, nausea
and vomiting, flu-like symptoms, anxiety/nervousness, and agitation. In addition,
chest pain, fatigue, and pallor have been reported during FLOLAN (epoprostenol sodium) therapy, and
a role for the drug in these events cannot be excluded.

Adverse Events During Chronic Administration for Idiopathic or Heritable PAH

In an effort to separate the adverse effects of the drug from the adverse effects
of the underlying disease, Table 4 lists adverse events that occurred at a rate
at least 10% greater on FLOLAN (epoprostenol sodium) in controlled trials.

Adverse Events During Chronic Administration for PAH/SSD

In an effort to separate the adverse effects of the drug from the adverse effects
of the underlying disease, Table 5 lists adverse events that occurred at a rate
at least 10% greater on FLOLAN (epoprostenol sodium) in the controlled trial.

Although the relationship to FLOLAN (epoprostenol sodium) administration has not been established,
pulmonary embolism has been reported in several patients taking FLOLAN (epoprostenol sodium) and there
have been reports of hepatic failure.

Adverse Events Attributable to the Drug Delivery System

Chronic infusions of FLOLAN (epoprostenol sodium) are delivered using a small, portable infusion
pump through an indwelling central venous catheter. During controlled PAH trials
of up to 12 weeks' duration, the local infection rate was about 18%, and the
rate for pain was about 11%. During long-term follow-up, sepsis was reported
at a rate of 0.3 infections/patient per year in patients treated with FLOLAN (epoprostenol sodium) .
This rate was higher than reported in patients using chronic indwelling central
venous catheters to administer parenteral nutrition, but lower than reported
in oncology patients using these catheters. Malfunctions in the delivery system
resulting in an inadvertent bolus of or a reduction in FLOLAN (epoprostenol sodium) were associated
with symptoms related to excess or insufficient FLOLAN (epoprostenol sodium) , respectively (see ADVERSE
REACTIONS: Adverse Events During Chronic Administration).

Observed During Clinical Practice

In addition to adverse reactions reported from clinical trials, the following
events have been identified during post-approval use of FLOLAN (epoprostenol sodium) . Because they
are reported voluntarily from a population of unknown size, estimates of frequency
cannot be made. These events have been chosen for inclusion due to a combination
of their seriousness, frequency of reporting, or potential causal connection
to FLOLAN (epoprostenol sodium) .

DRUG INTERACTIONS

Additional reductions in blood pressure may occur when FLOLAN (epoprostenol sodium) is administered
with diuretics, antihypertensive agents, or other vasodilators. When other antiplatelet
agents or anticoagulants are used concomitantly, there is the potential for
FLOLAN (epoprostenol sodium) to increase the risk of bleeding. However, patients receiving infusions
of FLOLAN (epoprostenol sodium) in clinical trials were maintained on anticoagulants without evidence
of increased bleeding. In clinical trials, FLOLAN (epoprostenol sodium) was used with digoxin, diuretics,
anticoagulants, oral vasodilators, and supplemental oxygen.

In a pharmacokinetic substudy in patients with congestive heart failure receiving
furosemide or digoxin in whom therapy with FLOLAN (epoprostenol sodium) was initiated, apparent oral
clearance values for furosemide (n = 23) and digoxin (n = 30) were decreased
by 13% and 15%, respectively, on the second day of therapy and had returned
to baseline values by day 87. The change in furosemide clearance value is not
likely to be clinically significant. However, patients on digoxin may show elevations
of digoxin concentrations after initiation of therapy with FLOLAN (epoprostenol sodium) , which may
be clinically significant in patients prone to digoxin toxicity.